Key result
Novel TPR-based vaccine inhibits platelet aggregation and prolongs thrombosis in mice without impairing hemostasis.
Why the study?
No thromboxane A2 receptor antagonists have been approved for clinical use despite the receptor's role in thrombotic disorders, motivating development of a novel vaccine approach.
Answers are grounded in this paper and cite their sources.
BACKGROUND: receptor (TPR) in the development of thrombotic disorders, none of the antagonists developed to date has been approved for clinical use. To this end, we have previously shown that an antibody targeted against TPR's ligand-binding domain inhibits platelet activation and thrombus formation, without exerting any effects on hemostasis. Thus, the goal of the present studies is to design a novel TPR-based vaccine, demonstrate its ability to trigger an immune response, and characterize its antiplatelet and antithrombotic activity. METHODS AND RESULTS: We used a mouse keyhole limpet hemocyanin/peptide-based vaccination approach rationalized over the TPR ligand-binding domain (ie, the C-terminus of the second extracellular loop). The biological activity of this vaccine was assessed in the context of platelets and thrombotic diseases, and using a host of in vitro and in vivo platelet function experiments. Our results revealed that the TPR C-terminus of the second extracellular loop vaccine, in mice: (1) triggered an immune response, which resulted in the development of a C-terminus of the second extracellular loop antibody; (2) did not affect expression of major platelet integrins (eg, glycoprotein IIb-IIIa); (3) selectively inhibited TPR-mediated platelet aggregation, platelet-leukocyte aggregation, integrin glycoprotein IIb-IIIa activation, as well as dense and α granule release; (4) significantly prolonged thrombus formation; and (5) did so without impairing physiological hemostasis. CONCLUSIONS: Collectively, our findings shed light on TPR's structural biological features, and demonstrate that the C-terminus of the second extracellular loop domain may define a new therapeutic target and a TPR vaccine-based approach that should have therapeutic applications.
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Alshbool et al. (2018) studied Thrombotic disorders. TPR-based vaccine was evaluated on Immune response, platelet function, and thrombus formation. A novel TPR-based vaccine in mice triggered an immune response, inhibited platelet aggregation, and prolonged thrombus formation without impairing physiological hemostasis.
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